Regulation of mitochondrial metabolism by the phosphorylation system and the complex IV and its impact on oxidative stress

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A large fraction of energy needed for heart and skeletal muscle contraction comes from oxidative phosphorylation (OXPHOS), a process that takes place in the inner mitochondrial membrane. OXPHOS couple the transfer of electrons in the electron transport system (ETS) to the movement of protons in the intermembrane space. The proton gradient formed is accumulated between the two mitochondrial membranes and is utilized by the phosphorylation system to produce energy in the form of ATP. The energy produced depends not only from the efficiency of electron transport between the complexes I to IV of the ETS but also of the ability of the phosphorylation system to convert the proton gradient into energy. For instance, previous studies showed that the phosphorylation system exert a strong control on OXPHOS in the human heart and skeletal muscle, whereas this particular characteristic is not shared with commonly used animal models such as mice and rats.**The proposed program studies the intra and interspecific variation in the regulatory mechanisms of mitochondrial metabolism and the link between the regulatory mechanisms and the oxidative stress. Understanding the difference in regulation of mitochondrial metabolism between species and cellular conditions and their consequences on oxidative stress is essential. If a general condition or a mutation modifies an ETS complex, the effect could be either minor if the mitochondria are regulated principally by the phosphorylation system, or dramatic if the species or the tissue has mitochondria controlled mainly by the ETS complexes. Identifying the species difference in the site of regulation of mitochondrial metabolism and the impact on oxidative stress is essential for an appropriate interpretation of the link between mitochondrial function and aging or muscle energy deficiencies.